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A strategy for uncovering germline variants altering anti-tumor CD8 T cell response

Journal of Genetics and Genomics 2023年第5期50卷 353-361页

作者： Vijay Kumar Ulaganathan Martina H.Vasileva klinik fur dermatologie&allergology Universitatsmedizin GottingenGottingen 37075Germany Institut fuir Multiple Sklerose Forschung NeuroimmunologieUniversitatsmedizin GottingenGottingen 37075Germany University of Lorraine NGERE UnitFaculte de Medecine9 Avenue de La Foret de HayeVandoeuvre-les-Nancy 54505France

Among many factors known to alter the outcomes of T cell receptor(TCR)-induced proximal signaling,the role of human germline variants in dictating the individuality of the anti-tumor CD8 T cell response has remained challenging to address.Here,we describe a convenient strategy for molecular and functional characterization of phosphotyrosine-altering non-synonymous single nucleotide variations(pTyr-SNVs)that directly impact TCR-induced proximal phosphotyrosine motif-based signaling pathways.We devise an experimental co-cultivation set-up comprising a C57BL/6 mouse-derived metastatic melanoma cell line engineered to constitutively present ovalbumin(OVA)antigens and retrovirally engineered syngeneic major histocompatibility complex(MHC)Class I restricted OVA TCR-transgenic CD8 T cells(OT-I).Using the synthetic version of pTyr-SNV rs1178800678-G/T-encoding integrin alpha 4(ITGA4)p.S1027I variant as a prototype,we show that under identical TCR stimulation conditions,genetically determined membrane-proximal immunoreceptor tyrosin activation motif(ITAM)results in increased tyrosine phosphorylation of 70 kDa zeta-chain-associated protein(ZAP70)and the levels of cytotoxic effector molecule granzyme B(GZMB),which in turn result in enhanced cytotoxic activity against metastatic melanoma cell line.This strategy paves the way for rapid molecular and functional characterization of anti-tumor immune response-linked germline pTyr-SNVs so as to improve our understanding of the genetic basis of individual-to-individual differences in anti-tumor CD8 T cell response.

关键词： Non-synonymous single nucleotide variants(nsSNVs) Membrane-proximal phosphotyrosine signalling motifs Phosphotyrosine-altering non-synonymous single nucleotide variants(pTyr-SNVs) Immunoreceptor tyrosine activation motif(ITAM) CD8 T cells Melanoma B16-F10

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Use of pCONUS HPC for the treatment of unruptured wide- necked bifurcation aneurysms: early clinical experience using single antiplatelet therapy

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Stroke & Vascular Neurology 2021年第1期6卷 57-64页

作者： Marta Aguilar Perez Victoria Hellstern Carmen Serna Candel Christina Wendl Hansjorg Bazner Oliver Gansladt Hans Henkes Neuroradiologische klinik NeurozentrumKlinikum StuttgartStuttgartGermany Institut fur Rontgendiagnostik Zentrum fur NeuroradiologieFakultat für Medizin der Universitat RegensburgRegensburgGermany Neurologische klinik NeurozentrumKlinikum StuttgartStuttgartGermany Neurochirurgische NeurozentrumKlinikum StuttgartStuttgartGermany Medizinische Fakultat Universitat Duisburg-EssenEssenGermany

Background In recent years,a growing number of stents and stent-like devices have become available to facilitate the treatment of challenging aneurysms.However,the need for dual antiplatelet therapy can limit their use,especially in ruptured aneurysms.The hydrophilic polymer coating(pHPC,phenox)is a novel glycan-based multilayer polymer that reduces platelet adhesion.This study aims to report our initial experience using the pCONUS HPC device for the treatment of unruptured wide-necked bifurcation aneurysms(WNBA)using acetylsalicylic acid(ASA)as single antiplatelet therapy(SAPT).Methods We retrospectively identified all patients who were treated with the pCONUS HPC for unruptured WNBA in a multi-staged procedure using ASA as SAPT.Records were made of periprocedural complications,clinical outcome and angiographic and clinical follow-up.Results We identified 15 patients with 15 WNBA.The average age was 69 years old(range,41-76).Seven aneurysms were located in the middle cerebral artery,five in the anterior communicating artery,two at the basilar tip and one in the posterior communicating artery.Immediate post-treatment angiography showed five aneurysms with modified Raymond-Roy classification(mRRC)grade Ⅰ and four aneurysms with mRRC grade Ⅱ.There were no haemorrhagic complications.Four patients developed thrombus formation during the second treatment session,all of them completely resolving after administration of glycoprotein Ⅱb/Ⅲa antagonists.Angiographic follow-up data were available for 10 patients and showed adequate occlusion(mRRC Ⅰ or Ⅱ)in eight aneurysms(80%).In-stent stenosis was observed in one patient whereas two patients showed de novo stenosis in one of the efferent branches.Conclusions This early experience on the use of the pCONUS HPC device suggests that it can be useful for treating unruptured WNBA under ASA as SAPT.further investigation with a randomised treatment registry and larger cohort is needed.

关键词： treatment bifurcation HPC

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Uber EKG-Kennzeichungen der atrioventrikul ren akzessorischen Leitungsbahnen von Rechtsmittelsepta und Linksmittelsepta

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2001年第1期21卷 26-29页

作者： WANG Lin Ouyang F *** klinikum Hamburg Deutschland Cappato R Hebe J Volkmer M Antz M Ernst S Kuck K H 王琳 Abteilung fur Innere Medizin Tongji Klinik Tongji Mediszinisches Institut Huazhong Universitat fur Wissenschaft und Technik *** klinikum Hamburg Deutschland

In der Studie wurden 20 Patienten mit AV-Reentry Tachykardie unter Einbezug einer mittelseptalen gelegenen atrioventricul ren akzessorischen Leitungsbahn(MS) eingeschlossen, die seit 4 Jahren in unserem Elektrophysiologischen Untersuchungslabor mittels Katheters erfolgreich abladiert wurden. Die 20 Patienten hatten 26 akzessorische Leitungsbahnen. Daunter waren 21 MS (rechtsmittelseptal (RMS) zu linksmittelseptal(LMS)=17:4). 18 akzessorische Leitungsbahnen waren offen. Die Lokalisation der akzessorischen Leitungsbahnen wurde aufgrund der Stelle erfolgreich abladiert bestimmt. Die Ergebnisse zeigten, da die RMS und LMS den gleichen Charakter in den meisten Ableitungen des EKGs hatten, und jedoch der wenige Unterschied bei diesen beiden akzessorischen Lritungsbahnen besteht. Wenn die positive Polaritat der Delta Welle in der Ableitung V 1 bei der Patienten mit MS auftritt, mu sich berlegen, ob die M glichkeit der Lokalisation der akzessorischen Leitungsbahn im Linksmittelseptum besteht.

关键词： Katheterablation rechtsmittelseptale gelegene akzessorische Leitungsbahn linksmittelseptale gelegene akzessorische Leitungsbahn

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Management of occluded self-expanding biliary metal stents in malignant biliary disease

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Hepatobiliary & Pancreatic Diseases International 2018年第1期17卷 49-54页

作者： Simon Nennstiel Isolde Tschurtschenthaler Bruno Neu Hana Algül Monther Bajbouj Roland M. Schmid Stefan von Delius Andreas Weber klinik und Poliklinik fur Innere Medizin Ⅱ Klinikum rechts der Isar der Technischen Universitar Manchen Ismaninger Straβe 22 Munich 81675 Germany Medizinische klinik II Krankenhaus Landshut-Achdorf Academic Teaching Hospital Technische Universitar Munchen Achdorferweg 3 Landshut 84036Germany

Background: Occlusion of self-expanding metal stents(SEMS) in malignant biliary obstruction occurs in up to 40% of patients. This study aimed to compare the different techniques to resolve stent occlusion in our collective of patients.Methods: Patients with malignant biliary obstruction and occlusion of biliary metal stent at a tertiary referral endoscopic center were retrospectively identified between April 1, 1994 and May 31, 2014. The clinical records were further analyzed regarding the characteristics of patients, malignant strictures, SEMS,management strategies, stent patency, subsequent interventions, survival time and case charges.Results: A total of 108 patients with biliary metal stent occlusion were identified. Seventy-nine of these patients were eligible for further analysis. Favored management was plastic stent insertion in 73.4% patients. Second SEMS were inserted in 12.7% patients. Percutaneous transhepatic biliary drainage and mechanical cleansing were conducted in a minority of patients. further analysis showed no statistically significant difference in median overall secondary stent patency(88 vs. 143 days, P = 0.069), median survival time(95 vs. 192 days, P = 0.116), median subsequent intervention rate(53.4% vs. 40.0%, P = 0.501)and median case charge(€5145 vs. €3473, P = 0.803) for the treatment with a second metal stent insertion compared to plastic stent insertion. In patients with survival time of more than three months,significantly more patients treated with plastic stents needed re-interventions than patients treated with second SEMS(93.3% vs. 57.1%, P = 0.037).Conclusions: In malignant biliary strictures, both plastic and metal stent insertions are feasible strategies for the treatment of occluded SEMS. Our data suggest that in palliative biliary stenting, patients especially those with longer expected survival might benefit from second SEMS insertion. Careful patient selection is important to ensure a proper decision for either management strategy.

关键词： Self-expanding metal stents Biliary tract neoplasms Endoscopic retrograde cholangiopancreatography Biliary tract diseases Complications

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Lipid lowering in patients 75 years and older

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World Journal of Cardiology 2021年第10期13卷 526-532页

作者： Umidakhon Makhmudova P Christian Schulze Harry R Davis Oliver Weingartner klinik fur Innere Medizin I Universitatsklinikum JenaJena 07747Germany Synergy Partners RD Solutions Synergy Partners RD SolutionsGaithersburgMD 20850United States

More than twenty years ago,knowledge about the importance of cholesterol absorption and the potential therapeutic effect of its inhibition led to the discovery and clinical application of the first and only cholesterol absorption inhibitor to date–ezetimibe.Since then,ezetimibe has become a well-recognized player in lipid-lowering therapy.Recent findings of IMPROVE-IT and EWTOPIA 75 imply that elderly patients over the age of 75 years in particular benefit from ezetimibe.This review summarizes the evidence,discusses the possible underlying pathophysiological mechanisms and calls for a change in future dyslipidemia guidelines.

关键词： Cholesterol Cholesterol absorption Cholesterol synthesis Ezetimibe Elderly

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Assessing the Malignancy of Hepataocellular Carcinoma in Cirrhosis Using the Hepatocellular Contrast Agent Gd-EOB-DTPA and Correlation with the Cytometric DNA Index

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Advances in Molecular Imaging 2013年第1期3卷 1-7页

作者： R.Rottgen S.Kobi C.Grieser F.Streitparth H.Al-Abadi A.Duerr W.Faber J.Pratschke P.Neuhaus B.Hamm L.Ludemann klinik fur Radiologie Charite’Campus Virchow Augustenburger Platz 1BerlinGermany klinik fur Allgemein-Visceral-und Transplantationschirurgie Charite’Campus Virchow Augustenburger Platz 1BerlinGermany klinik fur Visceral- Transplantations-und ThoraxchirurgieUniversitatsklinikum InnsbruckInnsbruckAustria Abteilung fur Strahlenphysik Universitatsklinikum EssenEssenGermany

Aim: Investigation whether the signal intensity of hepatocellular carcinoma (HCC) on dynamic magnetic resonance imaging (MRI) with hepatocellular contrast medium (CM) correlates with the histologic malignancy grade and cytometric DNA index. Material and Methods: MRI at 1.5 T with hepatocellular CM Gd-DTPA-EOB of 63 patients (52 men, 11 women;64.0 ± 8.5 years) with HCC in cirrhosis. SI of the tumor and liver tissue in sequences (T1, T1fs, T2fs, T1fs + CM (arterial, venous, late venous phase) were correlated like the asymmetry coefficient of the SI in the arterial and venous phases respective the native and late venous phases of the tumor with the histologic malignancy grade and DNA index indicating the grade of abnormal DNA steam line respective aneuploid DNA. Results: SI did not significantly correlate with the histologic malignancy grade or DNA index for precontrast or postcontrast images. There is a significant correlation for the asymmetry coefficient of the SI in the arterial and venous phases with the DNA-index (p values of 0.00089 (Pearson) and 0.0082 (Spearman). Conclusion: A highly arterialized hepatocellular carcinoma with rapid washout in the venous phase corresponds to a higher malignant potential. These findings suggest that the MR parameters investigated here may predict the malignant potential and prognosis of HCC before surgery.

关键词： Hepatocellular Carcinoma DNA Index DNA Cytometry Malignancy Grading

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不同患者群体容量反应性变量参数应用的强制性标准:重症监护病人窦性节律和控制呼吸流行情况的前瞻性研究（英文）

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2018年第7期19卷 515-524页

作者： Wolfgang HUBER Uli MAYR ANDreas UMGELTER Michael FRANZEN Wolfgang REINDL RolAND M.SCHMID Florian ECKEL Ⅱ. Medizinische klinik und Poliklinik Klinikum rechts der Isar der Technischen Universitat Munchen Ismaninger Straβe 22 D-81675 Miinchen Germany Universitatsklinik fur Innere Medizin I Salzburger Landeskliniken Universitatsklinikum Salzburg Mullner Hauptstraβe 48A-5020 Salzburg Austria Ⅱ. Medizinische klinik Universitatsklinikum Mannheim Theodor-Kutzer-Ufer 1-3 D-68167 Mannheim Germany klinik fur Innere Medizin RoMed Klinik Bad Aibling Harthauser Straβe 16 D-83043 Bad Aibling Germany

目的:通过对危重病人在入院后24小时内和整个重症监护过程中窦性心律和控制呼吸情况的调查,分析每搏量变异在评估危重病人容量反应的适用性,并探究每搏量变异度在败血症、肝硬化和胰腺炎病人中的适用性。创新点:通过探究窦性节律和控制... 详细信息

目的:通过对危重病人在入院后24小时内和整个重症监护过程中窦性心律和控制呼吸情况的调查,分析每搏量变异在评估危重病人容量反应的适用性,并探究每搏量变异度在败血症、肝硬化和胰腺炎病人中的适用性。创新点:通过探究窦性节律和控制呼吸情况评估每搏量变异度在重症监护病人临床上的适用性,弥补重症监护病人窦性节律和控制呼吸情况数据的空白。方法:在进行1241次热稀释法血流量测量前,对88位病人的窦性节律和控制呼吸情况进行调查。结论:每搏量变异度在主要的医疗重症监护病房中的适用性只约为25%~35%。两项强制性指标的流行性在重症监护病房的情况随时间的延长而降低。此外,每搏量变异度在胰腺炎和肝功能衰竭患者中的适用性尤其低。

关键词：血液动力学检测前负荷容量反应性每搏量变异度脉压变异

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Mutation Status of KRAS, BRAF, PIK3CA and Expression Level of AREG and EREG Identify Responders to Cetuximab in a Large Panel of Patient Derived Colorectal Carcinoma Xenografts of All Four UICC Stages

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Journal of Cancer Therapy 2013年第2期4卷 678-693页

作者： Paulina Pechanska M.Becker T.Mayr B.Hinzmann H.-P.Adams I.Klaman K.-H.Kretschmar K.Kretschmar K.Stecker R.Mantke R.Pauli J.Pertschy K.Hertel K.Ridwelski K.Hellwig M.Pross C.Radke I.Fichtner J.Hoffmann A.Rosenthal Signature Diagnostics AG PotsdamGermany Experimental Pharmacology&Oncology Berlin-Buch GmbH BerlinGermany Stadtisches klinikum Brandenburg GmbH Klinik fur Allgemein-und ViszeralchirurgieInstitut fur PathologieBrandenburg an der HavelGermany Katholisches Krankenhaus St.Johann Nepomuk Klinik fur Allgemeine ChirurgieErfurtGermany HELIOS klinikum Erfurt Institut fur PathologieErfurtGermany klinikum Magdeburg Klinik für Allgemein-und ViszeralchirurgieInstitut fur PathologieMagdeburgGermany DRK kliniken Berlin-Kopenik Klinik fur ChirurgieInstitut fur PathologieBerlinGermany Max Delbruck Center fur Molekulare Medizin(MDC) Experimentale PharmakologieBerlinGermany.

To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A subgroup of 67 xenograft models was treated with cetuximab, bevacizumab and oxaliplatin as single agents. Mutation status of KRAS (G12, G13, A146T), BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allelespecific real-time PCR. KRAS codon 61 was assessed by conventional sequencing. AREG and EREG expression levels were analyzed by real-time PCR expression assays. In the treatment experiment we observed response rates of 27% (18/67) for cetuximab, 3% (2/67) for bevacizumab, and 6% (4/67) for oxaliplatin. Classification based on KRAS, BRAF and PIK3CA mutation status identified 15 of the responders (sensitivity 83%, confidence interval at p = 0.05 (CI): 59% - 96%), and 38 nonresponders (specificity 78%, CI: 63% - 88%). If any mutation except in KRAS codon 13 were considered, the classifier reached sensitivity of 94% and specificity of 69%. We improved specificity of the classifiers to 90% and 86% respectively by adding AREG and EREG RNA expression thresholds retrospectively. In patient-derived xenograft models, we found a predictive classifier for response to cetuximab that is more accurate than established biomarkers. We confirmed its potential performance in primary human tumors. For patients, the classifier’s sensitivity promises increased response rates and its specificity limits unnecessary toxicity. Given the scope of our xenograft models across all UICC stages, this applies not only to mCRC but also to the adjuvant setting of earlier stages. The xenograft collection allows to mimic randomized phase II trials and to test novel drugs effectively as single agents or in combinations. It also enables the development of highly accurate companion diagnostics as demonstrated by us for cetuximab.

关键词： Colorectal Cancer Xenograft Mutation Biomarker Cetuximab

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Current Controversies and the State of the Art in Endovascular Treatment of Vascular Malformations

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Journal of Interventional Medicine 2018年第2期1卷 65-69页

作者： Wayne Yakes Alexis Yakes Fiona Rohlffs Krasnodar Ivancev The Yakes Vascular Malformation Center Universitares Herrzentrum Hamburg Klinik und Poliklinik fur Ge-fassmedizin Universitats Klinikum Hamburg-Eppendorf

Vascular anomalies constitute some of the most difficult diagnostic and therapeutic enigmas that can be encountered in the practice of medicine. The clinical presentations are extremely protean and can range from an a... 详细信息

关键词： Current Controversies and the State of the Art in Endovascular Treatment of Vascular Malformations AVM

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Functional analysis and drug response to zinc and D-penicillamine in stable ATP7B mutant hepatic cell lines

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World Journal of Gastroenterology 2016年第16期22卷 4109-4119页

作者： Gursimran Chandhok Judit Horvath Annu Aggarwal Mohit Bhatt Andree Zibert Hartmut HJ Schmidt klinik fur Transplantationsmedizin Universitatsklinikum Munster D-48149 Munster Germany Institut fur Humangenetik Westfalische Wilhelms-Universitat D-48149 Munster Germany Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute Mumbai 400103 India

AIM: To study the effect of anti-copper treatment for survival of hepatic cells expressing different ATP7 B mutations in cell culture. METHODS: The most common Wilson disease(WD) mutations p.H1069 Q, p.R778 L and p.C271*, found in the ATP7 B gene encoding a liver copper transporter, were studied. The mutations represent major genotypes of the United States and Europe, China, and India, respectively. A human hepatoma cell line previously established to carry a knockout of ATP7 B was used to stably express WD mutants. m RNA and protein expression of mutant ATP7 B, survival of cells, apoptosis, and protein trafficking were determined.RESULTS: Low temperature increased ATP7 B protein expression in several mutants. Intracellular ATP7 B localization was significantly impaired in the mutants. Mutants were classified as high, moderate, and no survival based on their viability on exposure to toxic copper. Survival of mutant p.H1069 Q and to a lesser extent p.C271* improved by D-penicillamine(DPA) treatment, while mutant p.R778 L showed a pronounced response to zinc(Zn) treatment. Overall, DPA treatment resulted in higher cell survival as compared to Zn treatment; however, only combined Zn + DPA treatment fully restored cell viability. CONCLUSION: The data indicate that the basic impact of a genotype might be characterized by analysis of mutant hepatic cell lines.

关键词： ATP7B D-penicillamine Zinc Mutations Wilson disease Therapy

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